JPH03181499A - Novel peptide - Google Patents
Novel peptideInfo
- Publication number
- JPH03181499A JPH03181499A JP1318739A JP31873989A JPH03181499A JP H03181499 A JPH03181499 A JP H03181499A JP 1318739 A JP1318739 A JP 1318739A JP 31873989 A JP31873989 A JP 31873989A JP H03181499 A JPH03181499 A JP H03181499A
- Authority
- JP
- Japan
- Prior art keywords
- peptide
- resin
- amino
- glu
- leu
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 31
- 108090000623 proteins and genes Proteins 0.000 claims 1
- 239000011347 resin Substances 0.000 abstract description 11
- 229920005989 resin Polymers 0.000 abstract description 11
- 150000001413 amino acids Chemical class 0.000 abstract description 8
- -1 butoxycarbonyl (Boc) amino Chemical class 0.000 abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 abstract description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 238000010532 solid phase synthesis reaction Methods 0.000 abstract description 3
- 238000010511 deprotection reaction Methods 0.000 abstract description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 abstract description 2
- IOPLHGOSNCJOOO-UHFFFAOYSA-N methyl 3,4-diaminobenzoate Chemical compound COC(=O)C1=CC=C(N)C(N)=C1 IOPLHGOSNCJOOO-UHFFFAOYSA-N 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- ZERULLAPCVRMCO-UHFFFAOYSA-N sulfure de di n-propyle Natural products CCCSCCC ZERULLAPCVRMCO-UHFFFAOYSA-N 0.000 abstract description 2
- RSWGJHLUYNHPMX-UHFFFAOYSA-N 1,4a-dimethyl-7-propan-2-yl-2,3,4,4b,5,6,10,10a-octahydrophenanthrene-1-carboxylic acid Chemical compound C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 abstract 1
- JZDHUJAFXGNDSB-WHFBIAKZSA-N Glu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O JZDHUJAFXGNDSB-WHFBIAKZSA-N 0.000 abstract 1
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 1
- 229940030600 antihypertensive agent Drugs 0.000 abstract 1
- 239000002220 antihypertensive agent Substances 0.000 abstract 1
- 230000008030 elimination Effects 0.000 abstract 1
- 238000003379 elimination reaction Methods 0.000 abstract 1
- 238000004108 freeze drying Methods 0.000 abstract 1
- 108010049041 glutamylalanine Proteins 0.000 abstract 1
- 238000004811 liquid chromatography Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000012071 phase Substances 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- 239000007790 solid phase Substances 0.000 abstract 1
- 229940024606 amino acid Drugs 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 101500027956 Homo sapiens Vasoactive intestinal peptide Proteins 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000006798 recombination Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-Tyrosine Natural products OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Natural products C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000004872 arterial blood pressure Effects 0.000 description 2
- 238000009739 binding Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229960002885 histidine Drugs 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- AQTUACKQXJNHFQ-LURJTMIESA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanedioic acid Chemical group CC(C)(C)OC(=O)N[C@H](C(O)=O)CCC(O)=O AQTUACKQXJNHFQ-LURJTMIESA-N 0.000 description 1
- PQMRRAQXKWFYQN-UHFFFAOYSA-N 1-phenyl-2-sulfanylideneimidazolidin-4-one Chemical compound S=C1NC(=O)CN1C1=CC=CC=C1 PQMRRAQXKWFYQN-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-Leucine Natural products CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 125000002066 L-histidyl group Chemical group [H]N1C([H])=NC(C([H])([H])[C@](C(=O)[*])([H])N([H])[H])=C1[H] 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- 235000019454 L-leucine Nutrition 0.000 description 1
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 1
- 125000000769 L-threonyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](O[H])(C([H])([H])[H])[H] 0.000 description 1
- 125000003798 L-tyrosyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 101100053822 Rattus norvegicus Zdhhc7 gene Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 101500022359 Sus scrofa Vasoactive intestinal peptide Proteins 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 241000609666 Tuber aestivum Species 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
- C12N9/1205—Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/57563—Vasoactive intestinal peptide [VIP]; Related peptides
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/70—Vectors or expression systems specially adapted for E. coli
- C12N15/71—Expression systems using regulatory sequences derived from the trp-operon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/827—Proteins from mammals or birds
- Y10S530/843—Digestive system
- Y10S530/844—Stomach; intestine
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S930/00—Peptide or protein sequence
- Y10S930/01—Peptide or protein sequence
- Y10S930/17—Vasoactive intestinal peptides; related peptides
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Microbiology (AREA)
- Medicinal Chemistry (AREA)
- Plant Pathology (AREA)
- Physics & Mathematics (AREA)
- Endocrinology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Vascular Medicine (AREA)
- Toxicology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野１
本発明は、新規な生理活性ペプチドに関するものである
。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application 1] The present invention relates to a novel physiologically active peptide.
［従来の技術および問題点］
現在、腸管由来のベプタイドホルモンが数多く知られて
おり、中でもＶＩＰは、血管拡張作用、血圧降下作用、
気管支拡張作用などの有用な薬理作用が知られている。[Prior art and problems] At present, many intestinal-derived peptide hormones are known, and among them, VIP has vasodilatory effects, antihypertensive effects,
It is known to have useful pharmacological effects such as bronchodilatory effects.
また、ヒトＶＩＰとブタＶＩＰが全く同一であるように
、動物種によるペプチド配列の変異が少なく、消化管以
外にも多くの器官でその存在が確認され、最近では、あ
る種の神経伝達物質として、認識されるようになって来
ている重要なペプタイドである。In addition, just as human VIP and pig VIP are exactly the same, there are few variations in the peptide sequence depending on the animal species, and its presence has been confirmed in many organs other than the gastrointestinal tract, and recently it has been used as a type of neurotransmitter. , is an important peptide that is beginning to be recognized.
しかし、天然のヒトＶＩＰは、その分子中にＭｅｔ（Ｌ
−メチオニン）残基を有するため酸化に対し不安定であ
るだけでなく、酵素分解により、不活化されるため、安
定化をもとめて各種の誘導体についての検討が為されて
いる。However, natural human VIP contains Met (L) in its molecule.
-Methionine) residues, it is not only unstable to oxidation, but also inactivated by enzymatic decomposition, so various derivatives have been studied in search of stabilization.
［問題点を解決するための手段］
本発明者は、ＶＩＰの活性を損なうことなく、また、特
殊なアミノ酸を導入することで経済効率の高い遺伝子組
換えによる生産を不可能にすることのないよう、天然の
ヒトＶＩＰ様活性を有するペプチドを得るべくそのペプ
チド配列について、種々検討を行った結果、下記式
Ｈｉｓ−９ｅｒ−Ａｓｐ−Ａｌａ−Ｖａｌ−Ｐｈｅ−Ｔ
ｈｒ−Ａｓｐ−Ａｓｎ−Ｔｙｒ−ＴｈｒＡｒｇ−Ｌｅｕ
−Ａｒｇ−Ｌｙｓ−Ｇｌｎ−Ｌｅｕ−Ａ ｌ ａ−
Ｖａ １−Ｌｙ ５−Ｌｙ ５−Ｔｙ ｒ−Ｌ
ｅ ｕ−Ａｓｎ−５ｅ ｒ−Ｉ １ｅ−Ｌｅｕ−
Ａｓｎ−Ｇｌｙ−ｒｏ−Ｒ
（但し、ここでＲは、Ｈまたは、Ｇｌｕまたは、Ｇｌｕ
−Ａｌａを表す。）
で表される新規ペプチドが、ヒトＶＩＰと同等以上の薬
理作用を有し、かつ生体内で安定であることを見いだし
、本発明を完成した。[Means for Solving the Problems] The present inventor has devised a method that does not impair the activity of VIP and does not make production by genetic recombination, which is highly economically efficient, impossible by introducing special amino acids. As a result of various studies on the peptide sequence in order to obtain a peptide with natural human VIP-like activity, we found that the following formula His-9er-Asp-Ala-Val-Phe-T
hr-Asp-Asn-Tyr-ThrArg-Leu
-Arg-Lys-Gln-Leu-Alia-
Va 1-Ly 5-Ly 5-Tyr-L
e u-Asn-5e r-I 1e-Leu-
Asn-Gly-ro-R (where R is H, Glu or Glu
- represents Ala. The inventors have completed the present invention by discovering that a novel peptide represented by the following formula has a pharmacological effect equivalent to or higher than that of human VIP and is stable in vivo.
即ち、本発明は、下記式
％式％
）
で表される新規ペプチド（以下、本発明の化合物と称す
る）である。That is, the present invention is a novel peptide (hereinafter referred to as the compound of the present invention) represented by the following formula %.
上述した本発明の化合物の構造式、および以下の説明に
おいては、Ｈｉｓは、Ｌ−ヒスチジン、Ｓｅｒは、Ｌ−
セリン、ＡｓｐはＬ−アスパラギン酸、ＡｌａはＬ−ア
ラニン、Ｖａｌは、Ｌ−バリン、Ｐｈｅは、Ｌ−７ｘニ
ルアラニン、Ｔｈｒは、Ｌスレオニン、Ａｓｎは、Ｌ−
アスパラギン、Ｔｙｒは、Ｌ−チロシン、Ａｒｇは、Ｌ
−アルギニン、Ｌｅｕは、Ｌ−ロイシン、Ｌｙｓは、Ｌ
−リジン、Ｇｉｎは、Ｌ−グルタミン、ｌｉｅは、Ｌ−
インロイシン、Ｇｌｙは、グリシン、Ｐｒｏは゛、Ｌ−
プロリン、Ｇｌｕは、Ｌ−グルタミン酸の各残基をそれ
ぞれ意味する。In the structural formula of the compound of the present invention described above and the following explanation, His is L-histidine, and Ser is L-histidine.
Serine, Asp is L-aspartic acid, Ala is L-alanine, Val is L-valine, Phe is L-7xnylalanine, Thr is L-threonine, Asn is L-
asparagine, Tyr is L-tyrosine, Arg is L
-Arginine, Leu is L-leucine, Lys is L
-Lysine, Gin is L-glutamine, lie is L-
Inleucine, Gly is glycine, Pro is ゛, L-
Proline and Glu each refer to each residue of L-glutamic acid.
本発明の化合物は、液相法、固相法による一般的なペプ
タイドの有機化学合成法によって製造できるが、大腸菌
等を用いた遺伝子組換え法により、生産できると構造を
有しているので、遺伝子組換え法により生産するのこと
も可能である。The compound of the present invention can be produced by a general organic chemical synthesis method of peptides using a liquid phase method or a solid phase method, but since it has a structure that can be produced by a genetic recombination method using Escherichia coli etc. It is also possible to produce it by genetic recombination.
以下に、本発明の新規ペプチドの製造方法について、説
明する。The method for producing the novel peptide of the present invention will be explained below.
本発明の化合物は、ペプチド合成に用いられる固相法、
液相法等の通常一般的に用いられるアミノ酸の縮合方法
で合成することができる。例えば、その１例を挙げると
次の如くである。The compounds of the present invention can be used in solid-phase methods used for peptide synthesis;
It can be synthesized by a commonly used amino acid condensation method such as a liquid phase method. For example, one example is as follows.
Ｎ末アミノ酸に対応する市販の、またはｔｅｒｔ−ブト
キシカルボニル−Ｌ−アミノの酸（以下ＢＯＣアミノ酸
と略称する）と４−（オキシメチル）フェニルアセトア
ミドメチル樹脂を常法に従って結合させて得たＢｏｃ−
アミノ酸の結合した４−（オキシメチル）フェニルアセ
トアミドメチル樹脂を原料とし、これに、必要に応じて
アミノ基、カルボキシル基、水酸基を保護したＢｏｃ−
アミノ酸を所望の配列に従って順次結合させて粗ペプチ
ドを得、この粗ペプチドを精製することで得ることがで
きる。Boc- obtained by bonding a commercially available or tert-butoxycarbonyl-L-amino acid (hereinafter abbreviated as BOC amino acid) corresponding to the N-terminal amino acid and 4-(oxymethyl)phenylacetamidomethyl resin according to a conventional method.
The raw material is 4-(oxymethyl)phenylacetamidomethyl resin bound to an amino acid, and Boc-
It can be obtained by sequentially linking amino acids according to a desired sequence to obtain a crude peptide, and then purifying this crude peptide.
ここで、アミ７基、イミノ基、カルボキシル基および水
酸基の保護に当たっては、適当な保護基、例えばアミノ
基およびイミノ基は、ｐ−トルエンスルホニル基または
２−クロロベジルオキシカルポニル基で保護し、カルボ
キシル基は、β−シクロヘキシル基またはγ−ベンジル
基で保護し、水酸基は、ベンジル基または２．６−ジク
ロロベンジル基で保護したものを用いる。Here, in protecting the amine 7 group, imino group, carboxyl group and hydroxyl group, the amino group and imino group are protected with a p-toluenesulfonyl group or 2-chlorobenzyloxycarponyl group, The carboxyl group is protected with a β-cyclohexyl group or a γ-benzyl group, and the hydroxyl group is protected with a benzyl group or a 2,6-dichlorobenzyl group.
［実施例１
実施例１゜
Ｂｏａ−Ｌ−アラニンの結合した４−（オキシメチル）
フェニルアセトアミドメチル樹脂（アプライドバイオシ
ステム社製）０．５ｍｍｏｌを塩化メチレン中、５０％
トリフロロ酢酸で処理して、Ｂ。[Example 1 Example 1 Boa-L-alanine-bonded 4-(oxymethyl)
Phenylacetamidomethyl resin (manufactured by Applied Biosystems) 0.5 mmol in methylene chloride at 50%
B by treatment with trifluoroacetic acid.
Ｃ基をはずし、Ｏ−ベンジル−Ｂｏｃ−Ｌ−グルタミン
酸（アプライドバイオシステム社製）２ｍｍｏｌをジシ
クロへキシルカルボジイミドを用いて結合させた。The C group was removed, and 2 mmol of O-benzyl-Boc-L-glutamic acid (manufactured by Applied Biosystems) was bonded using dicyclohexylcarbodiimide.
以下、Ｂｏａ−アミノ酸を、Ｐ ｒ ｏ ｓ Ｇ Ｉ
Ｙ ５Ａｓｎ１Ｌｅｕ１１１ｅ、Ｓｅｒ、Ａｓｎ。Hereinafter, Boa-amino acid is expressed as P r o s G I
Y 5Asn1Leu111e, Ser, Asn.
Ｌｅｕ、ＴｙｒｌＬｙｓ、Ｌｙｓ、Ｖａ １％Ａｌａ、
Ｌｅｕ、Ｇ１ｎ１Ｌｙｓ、Ａｒｇ。Leu, TyrlLys, Lys, Va 1%Ala,
Leu, G1n1Lys, Arg.
ＬｅｕｌＡｒｇ、Ｔｈｒ、ＴｙｒｌＡａｎ。LeulArg, Thr, TyrlAan.
ＡｓｐＳＴｈｒ、Ｐｈｅ、Ｖａ Ｉ、Ａｌａ。AspSThr, Phe, Va I, Ala.
Ａｓｐｓ Ｓ ｅ ｒ ｚ Ｈ１ｓの順で結合させ反応
液を得 ｔこ 。Asps Serz H1s were combined in this order to obtain a reaction solution.
以上の反応は、アプライドバイオシステム社製のペプチ
ドシンセサイザーモデル４３０Ａにより行った。The above reaction was performed using a peptide synthesizer model 430A manufactured by Applied Biosystems.
結合反応終了後、この樹脂をアニソールおよびエチルメ
チルスルフィドの存在下、フッ化水素酸を加え、−２０
℃で３０分、ついで０℃で１０分間反応させて、脱保護
および樹脂からの脱離を行い、２Ｎ−酢酸を用いて溶解
し、凍結乾燥後、逆相ＨＰＬＣにより精製して、
Ｈｉ ５−５ｅ ｒ−Ａｓ ｐ−Ａ ｌ ａ−Ｖａ Ｉ
−Ｐｈｅ−Ｔｈｒ−Ａｓｐ−Ａｓｎ−Ｔｙｒ−Ｔｈｒ−
Ａｒｇ−Ｌｅｕ−Ａｒｇ−Ｌｙｓ−Ｇｌｎ−Ｌｅｕ−Ａ
ｌ ａ−Ｖａ １−Ｌｙ ５−Ｌｙ ５−Ｔｙ ｒ−
Ｌｅ ｕＡｓｎ−５ｅｒ−１１ｅ−Ｌｅｕ−Ａｓｎ−Ｃ
１ｙ−Ｐｒｏ−Ｇｌｕ−Ａｌａ、４０ｍｇを白色粉末と
して得ｔこ。After the binding reaction, hydrofluoric acid was added to this resin in the presence of anisole and ethyl methyl sulfide, and the resin was heated to -20
℃ for 30 minutes and then 0℃ for 10 minutes to perform deprotection and release from the resin, dissolve using 2N-acetic acid, freeze-dry, and purify by reverse-phase HPLC to obtain Hi 5- 5e r-As p-A l a-Va I
-Phe-Thr-Asp-Asn-Tyr-Thr-
Arg-Leu-Arg-Lys-Gln-Leu-A
l a-Va 1-Ly 5-Ly 5-Tyr-
LeuAsn-5er-11e-Leu-Asn-C
1y-Pro-Glu-Ala, 40 mg was obtained as a white powder.
実施例２゜
Ｏ−ベンジル＝Ｂｏｃ−Ｌ−グルタミン酸の結合した４
−（オキシメチル）フェニルアセトアミドメチル樹脂（
アプライドバイオシステム社製）０゜５ｍｍｏｌを塩化
メチレン中、５０％トリフ０口酢酸で処理して、Ｂｏａ
基をはずし、Ｂｏｃ−Ｌ−プロリン（アプライドバイオ
システム社製）２ｍｍｏｌをシンクロヘキシルカルボジ
イミドを用いて結合させ Ｉこ 。Example 2 O-benzyl=Boc-L-glutamic acid bonded 4
-(oxymethyl)phenylacetamidomethyl resin (
Boa
After removing the group, 2 mmol of Boc-L-proline (manufactured by Applied Biosystems) was bonded using synchhexylcarbodiimide.
以下、Ｂｏｃ−アミノ酸を、Ｇａｙ、Ａｓｎ。Hereinafter, Boc-amino acids are referred to as Gay and Asn.
Ｌｅｕ、 Ｉ ｌｅ、 Ｓｅｒ、
Ａｓｎ ％ Ｌｅｕ。Leu, I le, Ser,
Asn% Leu.
Ｔｙ ｒ、 Ｌｙ ｓ Ｓ Ｌｙ
ｓ、 Ｖａ ｌ、 Ａ ｌ ａ。Tyr, Ly s S Ly
s, Val, Al a.
Ｌ ｅ ｕ ｓ Ｇ Ｉ ｎ ％
Ｌ ｙ ｓ ｓ Ａ ｒ ｇ
Ｓ Ｌ ｅ ｕ ％Ａｒｇ、 Ｔｈｒ、
Ｔｙｒ、 Ａｓｎ、 Ａｓｐ。L eu s G I n %
L yss A r g
S L eu %Arg, Thr,
Tyr, Asn, Asp.
Ｔｈ ｒ、 Ｐｈｅ、 Ｖａ Ｉ
、 Ａｌａ、Ａｓ１）ｘＳｅｔ％Ｈｉｓの順で結合さ
せ反応液を得た。Thr, Phe, Va I
, Ala, As1)xSet%His were combined in this order to obtain a reaction solution.
以上の反応は、アプライドバイオシステム社製のペプチ
ドシンセサイザーモデル４３０Ａにより行った。The above reaction was performed using a peptide synthesizer model 430A manufactured by Applied Biosystems.
以下、実施例１と同様に処理して、
Ｈｉ ５−５ｅ ｒ−Ａｓ ｐ−Ａ Ｉ ａ−Ｖａ Ｉ
−Ｐｈｅ−Ｔｈｒ−Ａｓｐ−Ａｓｎ−Ｔｙｒ−Ｔｈｒ−
Ａｒｇ−Ｌｅｕ−Ａｒｇ−Ｌｙｓ−Ｇｌｎ−Ｌｅｕ−Ａ
ｌａ−Ｖａ Ｉ−Ｌｙｓ−Ｌｙｓ−Ｔｙｒ−Ｌｅｕ−
Ａｓｎ−３ｅｒ−Ｉ １ｅ−Ｌｅｕ−Ａｓｎ−Ｇｌｙ
−Ｐｒｏ−Ｇｌｕ、５０ｍｇを白色粉末として得た。Hereinafter, the same treatment as in Example 1 was performed to obtain Hi 5-5e r-As p-A I a-Va I
-Phe-Thr-Asp-Asn-Tyr-Thr-
Arg-Leu-Arg-Lys-Gln-Leu-A
la-Va I-Lys-Lys-Tyr-Leu-
Asn-3er-I 1e-Leu-Asn-Gly
-Pro-Glu, 50 mg was obtained as a white powder.
実施例３゜
Ｂｏｃ−Ｌ−プロリンの結合しｆニー ４− （オキシ
メチル）フェニルアセトアミドメチル樹脂（アプライド
バイオシステム社製）０．５ｍｍｏｌを塩化メチレン中
、５０％トリフ０口酢酸で処理して、Ｂ。Example 3 0.5 mmol of Boc-L-proline bonded 4-(oxymethyl)phenylacetamidomethyl resin (manufactured by Applied Biosystems) was treated with 50% truffle acetic acid in methylene chloride. B.
Ｃ基をはずし、Ｂｏａ−グリシン（アプライドバイオシ
ステム社製）２ｍｍｏｌをジシクロへキシルカルボジイ
ミドを用いて結合させた。The C group was removed, and 2 mmol of Boa-glycine (manufactured by Applied Biosystems) was bonded using dicyclohexylcarbodiimide.
以下、Ｂｏａ−アミノ酸を、Ａｓｎ５ Ｌｅｕ。Hereinafter, Boa-amino acids are referred to as Asn5 Leu.
Ｉ ｆｅｎ ５ｅｒｓ Ａｓｎ５ ＬｅｕＳＴｙｒｌＬ
ｙｓ、Ｌｙｓ、Ｖａ １ＳＡｌａ、ＬｅｕｓＧｉｎ、Ｌ
ｙｓ、Ａｒｇ、ＬｅｕｌＡｒｇｌＴｈ ｒ、Ｔｙ ｒ、
Ａｓ ｎ、Ａｓ Ｉ）ＸＴｈ ｒ。I fen 5ers Asn5 LeuSTyrlL
ys, Lys, Va 1SAla, LeusGin, L
ys, Arg, LeulArglTh r, Tyr,
As n, As I)XTh r.
ＰｈｅＳＶａｌ、Ａｌａ、Ａｓｐ、Ｓｅｒ。PheSVal, Ala, Asp, Ser.
Ｈｉｓの順で結合させ反応液を得た。A reaction solution was obtained by binding in the order of His.
以上の反応は、アプライドバイオシステム社製のペプチ
ドシンセサイザーモデル４３０Ａにより行った。The above reaction was performed using a peptide synthesizer model 430A manufactured by Applied Biosystems.
以下、実施例１と同様に処理して、
Ｈｉ ５−３ｅ ｒ−Ａｓ ｐ−Ａｌ ａ−Ｖａ ｌ−
Ｐｈｅ−Ｔｈｒ−Ａｓｐ−Ａｓｎ−Ｔｙｒ−Ｔｈｒ−Ａ
ｒｇ−Ｌｅｕ−Ａｒｇ−Ｌｙｓ−Ｇｌｎ−Ｌｅｕ−Ａ
ｌ ａ−Ｖａ １−Ｌｙ ５−Ｌｙ ５−Ｔｙ ｒ−Ｌ
ｅ ｕＡｓｎ−５ｅｒ−Ｉ １ｅ−Ｌｅｕ−Ａｓｎ−Ｇ
ｌｙ−Ｐｒｏ、５０ｍｇを白色粉末として得た。Hereinafter, the same treatment as in Example 1 was carried out to obtain Hi 5-3e r-As p-Ala-Val-
Phe-Thr-Asp-Asn-Tyr-Thr-A
rg-Leu-Arg-Lys-Gln-Leu-A
l a-Va 1-Ly 5-Ly 5-Tyr-L
e uAsn-5er-I 1e-Leu-Asn-G
ly-Pro, 50 mg was obtained as a white powder.
以上のようにして生産されたペプチドの構造は、アミノ
酸配列をベプチドシークエンサー（アプライドバイオシ
ステム社製・モデル４７７Ａ）により、ニドマン分解し
て得られたフェニルチオヒダントイン（ＰＴＨ）アミノ
酸を逆相ＨＰＬＣで分析することにより所望のアミノ酸
配列を有することを確認した。The structure of the peptide produced as described above was obtained by subjecting the amino acid sequence to phenylthiohydantoin (PTH) amino acid obtained by Nidoman degradation using a peptide sequencer (Model 477A manufactured by Applied Biosystems) using reversed-phase HPLC. By analysis, it was confirmed that it had the desired amino acid sequence.
［発明の効果Ｊ
次に、本発明のペプチドが降圧作用を示すことを実験例
を挙げて説明する。[Effect of the Invention J Next, the fact that the peptide of the present invention exhibits a hypotensive effect will be explained with reference to experimental examples.
実験例
〈ラットの血圧に及ぼす影響〉
本発明のペプチドを、５週令のＩＣＲ系雄性マウスの尾
静脈に４０μｇ／ｋｇ投与し、投与後５． １０．２０
．３０分における尾動脈血圧を非観血式血圧測定装置（
ＴＫ−１５０）を用いて測定し、表１の結果が得られた
。Experimental Example <Effect on Blood Pressure of Rats> The peptide of the present invention was administered at a dose of 40 μg/kg into the tail vein of 5-week-old male ICR mice. 10.20
．． The tail artery blood pressure was measured at 30 minutes using a non-invasive blood pressure measuring device (
TK-150), and the results shown in Table 1 were obtained.
表１
表ＩＪこ示したように、生理食塩水投与における尾動脈
血圧を１００％とした場合の本発明のペプチド投与時の
血圧は、天然型のＶＩＰ投与時の血圧よりも低く、その
強い降圧作用が示されたばかりでなく、持続作用も認め
られ、本発明のペプチドの医療応用上の有用性が示され
た。Table 1 Table IJ As shown in Table IJ, the blood pressure when the peptide of the present invention was administered was lower than that when the native VIP was administered, assuming that the tail artery blood pressure after physiological saline administration was 100%, and the blood pressure was lower than that when the native VIP was administered. Not only an action was demonstrated, but a sustained action was also observed, demonstrating the usefulness of the peptide of the present invention in medical applications.
本発明のペプチドは、注射剤として用いることができ、
注射剤を製造する場合には、希釈剤として、一般に注射
用蒸留水、生理食塩水、デキストロース水溶液、注射用
植物油、プロピレングリコール、ポリエチレングリコー
ル等を用いることができる。さらに、必要に応じて、適
宜、等張化剤、安定剤、防腐剤、無痛化剤等を加えても
よい。The peptide of the present invention can be used as an injection,
When producing an injection, diluents that can generally be used include distilled water for injection, physiological saline, aqueous dextrose solution, vegetable oil for injection, propylene glycol, polyethylene glycol, and the like. Furthermore, an isotonizing agent, a stabilizer, a preservative, a soothing agent, etc. may be added as appropriate.
また、本発明のペプチドは、ネブライザー、吸入器等を
用いて、鼻粘膜、気管支に直接投与することもできる。Furthermore, the peptide of the present invention can also be directly administered to the nasal mucosa or bronchus using a nebulizer, inhaler, or the like.
また、本発明のペプチドは、浸透補助剤等とともに、外
用剤として用いることもできる。Furthermore, the peptide of the present invention can also be used as an external preparation together with a penetration aid and the like.
更に、本発明の化合物は、薬理学上使用し得る酸または
塩基を用いた塩として使用することもできる。Furthermore, the compounds of the present invention can also be used as salts with pharmacologically usable acids or bases.
Claims (1)
−Ａｌａを表す。） で表される新規ペプチド。[Claims] The following formula [There is a gene sequence] (where R is H, Glu, or Glu
- represents Ala. ) A novel peptide represented by.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1318739A JPH03181499A (en) | 1989-12-11 | 1989-12-11 | Novel peptide |
| EP91109469A EP0517931B1 (en) | 1989-12-11 | 1991-06-10 | Physiologically active peptides, use thereof and a method of producing said peptides |
| US07/710,882 US5166316A (en) | 1989-12-11 | 1991-06-10 | Physiologically active peptides and a method of producing peptides |
| US07/925,732 US5316919A (en) | 1989-12-11 | 1992-08-07 | Method of producing 2 KD to 10 KD peptides having no L-methionine residue |
| EP95114382A EP0763598A1 (en) | 1989-12-11 | 1995-09-13 | Method of preparing a fusion protein |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1318739A JPH03181499A (en) | 1989-12-11 | 1989-12-11 | Novel peptide |
| EP95114382A EP0763598A1 (en) | 1989-12-11 | 1995-09-13 | Method of preparing a fusion protein |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03181499A true JPH03181499A (en) | 1991-08-07 |
Family
ID=26138802
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1318739A Pending JPH03181499A (en) | 1989-12-11 | 1989-12-11 | Novel peptide |
Country Status (3)
| Country | Link |
|---|---|
| US (2) | US5166316A (en) |
| EP (2) | EP0517931B1 (en) |
| JP (1) | JPH03181499A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0624190A4 (en) * | 1992-01-21 | 1995-04-19 | Cryopharm Corp | Method of freezing cells and cell-like materials. |
| FR2701953B1 (en) * | 1993-02-22 | 1995-05-24 | Centre Nat Rech Scient | Multi-VIP fusion protein and method for preparing recombinant VIP. |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP179892C1 (en) | 1948-04-28 | 1949-07-20 | ||
| JPS62246595A (en) * | 1986-04-17 | 1987-10-27 | Eisai Co Ltd | Peptide having bronchodilative action and depressive action |
| JPS63179892A (en) * | 1987-01-19 | 1988-07-23 | Daicel Chem Ind Ltd | Vip hydrochloride and production thereof |
| JPH01296996A (en) * | 1988-05-26 | 1989-11-30 | Akira Kaji | Novel peptide |
| JPH02249489A (en) * | 1989-03-24 | 1990-10-05 | Yakult Honsha Co Ltd | Vector for expressing exogenote fragment |
| US5141924A (en) * | 1989-06-30 | 1992-08-25 | Hoffmann-La Roche, Inc. | Synthetic vasoactive intestinal peptide analogs |
| JPH04346790A (en) * | 1991-05-22 | 1992-12-02 | Akira Kaji | New production method of peptide |
-
1989
- 1989-12-11 JP JP1318739A patent/JPH03181499A/en active Pending
-
1991
- 1991-06-10 US US07/710,882 patent/US5166316A/en not_active Expired - Fee Related
- 1991-06-10 EP EP91109469A patent/EP0517931B1/en not_active Expired - Lifetime
-
1992
- 1992-08-07 US US07/925,732 patent/US5316919A/en not_active Expired - Fee Related
-
1995
- 1995-09-13 EP EP95114382A patent/EP0763598A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP0763598A1 (en) | 1997-03-19 |
| EP0517931B1 (en) | 1996-11-20 |
| US5316919A (en) | 1994-05-31 |
| US5166316A (en) | 1992-11-24 |
| EP0517931A1 (en) | 1992-12-16 |
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